Cushing's syndrome refers to the clinical manifestations induced by chronic exposure to excess glucocorticoids. There are three pathological conditions that can result in the chronic overproduction of endogenous cortisol in man: the most frequent is Cushing's disease where adrenocorticotropic hormone (ACTH) is overproduced by a pituitary corticotroph adenoma, rarely ACTH can be produced in an 'ectopic' manner by a non-pituitary tumour, finally cortisol can be directly over-secreted by one or (rarely) the two adrenals that have become tumourous, either benign or malignant. The positive diagnosis of Cushing's syndrome requires that chronic hypercortisolism is unequivocally demonstrated biologically, using 24-h urinary cortisol, late-evening plasma or salivary cortisol, midnight 1-mg or the classic 48-h-low-dose dexamethasone suppression test, etc., all with essentially the same diagnosis potencies. The search for the responsible tumour then relies on the assessment of the corticotroph function, and imaging: suppressed ACTH plasma levels indicate an 'adrenal' Cushing, and the responsible unilateral adrenocortical tumour is always visible at computed tomography (CT) scan, whereas its benign or malignant nature may be difficult to diagnose before surgery. Imaging can suspect bilateral 'adrenal' Cushing, when the two adrenals are small, as in the primary pigmented nodular adrenal dysplasia associated with Carney complex, or enlarged, as in the ACTH-independent macronodular adrenocortical hyperplasia. Measurable or increased ACTH plasma levels indicate either Cushing's disease or the ectopic ACTH syndrome. When the dynamics of the corticotroph function (high-dose dexamethasone suppression test, the CRH test) are equivocal, and/or the imaging is non-contributive, it may be difficult to distinguish between the two. This is the situation where sampling ACTH plasma levels in the inferior petrosal sinus may be necessary. The best treatment option of Cushing's disease is when the responsible corticotroph adenoma can be entirely removed by the trans-sphenoidal approach, with sufficient skill to preserve the normal anterior pituitary function. When it fails, all other options directed towards the pituitary (radiation therapies), or the adrenals (medications or surgery), have numerous side effects. There is at present no recognised efficient medical treatment towards the corticotroph adenoma -still an orphan disease.